Stoetly Chapter 34 Antiemetics

Question 1

Pathophysiology

• Patients with nausea have a subjective feeling of the need to vomit; the sensation is very, very unpleasant.
• Emesis is not always preceded by nausea.
  
  • Vomiting typically begins with contractions of the ileum and jejunum, moving their contents back toward the _______(1).
  • The glottis is then closed, protecting the airway, and the diaphragm contracts, creating negative intrathoracic pressure as the pharyngeal sphincters relax.
  • Under pressure and with open upper sphincters, emesis occurs
• When the stomach is empty, retching or dry heaves occur, which involves the same process that happens, but no stomach contents are expelled.
• _______(2) is different from regurgitation in which the sphincters are not completely closed and the stomach contents can pass into the esophagus in the setting of elevated abdominal pressure such as might occur during excessive mask _______(3).
• The highly choreographed sequence that occurs during vomiting and retching is controlled by the vomiting center.
  
  • It consists of the nucleus of the tractus solitarius and parts of the reticular formation in the medulla oblongata.
  • A number of neurotransmitters activate and inhibit activity of the vomiting center, including _______(4).
    
    • Drugs that are used to control nausea and vomiting modulate the activity of these receptors.
• The chemoreceptor trigger zone (CRTZ) located in the area _______(5) is outside the blood–brain barrier.

Answer 1

1. stomach
2. ventilation
3. Emesis
4. acetylcholine, dopamine, histamine, substance P, and serotonin
5. postrema on the floor of the fourth ventricle

Question 2

• The interaction with the vestibular apparatus could create the common interaction between vertigo and vomiting whereas the cerebral cortex could induce psychogenic vomiting.
• Upon activation, the vomiting center sends efferent signals via the cranial nerves _______(1) through the vagal parasympathetic fibers and sympathetic chain and to skeletal muscle through α motor neurons.
  
  • Signals from the vomiting center via these nerves trigger the complex motor process resulting in emesis.

5-HT3 Receptor Antagonists:
- The 5-HT3 receptors are excitatory ligand-gated nonselective cation channels.
- Serotonin is released from the _______(2) cells of the small intestine, stimulates the vagal afferents through 5-HT3 receptors, and initiates the vomiting reflex.
- Antagonists of these receptors have antiemetic effects.

Clinical Uses
- The 5-HT3 receptor antagonists (ondansetron, tropisetron, granisetron, dolasetron) represent a significant advance in the prophylaxis and treatment of nausea and vomiting are useful antiemetics in the prophylaxis and treatment of chemotherapy (CINV) and radiation therapy–induced nausea and vomiting and are equally effective in the prevention and treatment of PONV.
- The 5-HT3 receptor antagonists, however, are not effective in the treatment of nausea and vomiting caused by _______(3) stimulation.

Answer 2

1. V, VII, IX, X, and XII
2. enterochromaffin
3. vestibular

Question 3

• Comparison with other Antiemetics
  • Ondansetron (4 mg), dexamethasone (4 mg), or droperidol (1.25 mg) administered intravenously (IV) as prophylactic therapy before induction of general anesthesia are equally effective in decreasing the incidence of PONV by about 26%
    
    • 5-HT3 antagonists are deemed the “gold standard” for antiemetics
• Pharmacokinetics
  
  • Blah XD
• Ondansetron
  
  • Ondansetron is a carbazolone derivative that is structurally related to serotonin and possesses specific 5-HT3 subtype receptor antagonist properties without altering dopamine, histamine, adrenergic, or cholinergic receptor activity
    
    • As a result, ondansetron is free of neurologic side effects common to _______(1) and metoclopramide.
  • The most commonly reported side effects from treatment with ondansetron are _______(2).
  • Cardiac arrhythmias and conduction disturbances (atrioventricular block) have been reported after the IV coadministration of ondansetron and metoclopramide.
  • Ondansetron, 4 to 8 mg IV (administered over 2-5 minutes immediately before the induction of anesthesia), is highly effective in decreasing the incidence of PONV in a susceptible patient population (ambulatory gynecologic surgery, middle ear surgery).
  • Use of _______(3) for induction and maintenance of anesthesia is almost as effective as ondansetron in preventing PONV (19% vs 26%, respectively) and ondansetron continues to have antiemetic effects when used in a propofol-based anesthetic.

Answer 3

1. droperidol
2. headache and diarrhea
3. propofol

Question 4

Anticholinergics

• Muscarinic acetylcholine receptors are found in the vestibular system near the CRTZ.
  
  • Activation of this receptor results in activation of the CRTZ resulting in nausea.
  • Anticholinergics prevent this pathway resulting in its antiemetic effects.
  • One of the most commonly used perioperative anticholinergic antiemetic is scopolamine.
• Central Anticholinergic Syndrome
  
  • _______(1) can enter the central nervous system (CNS) and produce symptoms characterized as the central anticholinergic syndrome.
  • Symptoms range from restlessness and hallucinations to somnolence and unconsciousness
    
    • Presumably, these responses reflect blockade of muscarinic cholinergic receptors and competitive inhibition of the effects of acetylcholine in the CNS
    • _______(2) does not easily cross the blood–brain barrier and thus is not likely to cause central anticholinergic syndrome.
  • Central anticholinergic syndrome has been attributed to the IV administration of anticholinergic drugs before the induction of anesthesia.
  • _______(3), a lipid-soluble tertiary amine anticholinesterase drug administered in doses of 15 to 60 µg/kg IV, is a specific treatment for the central anticholinergic syndrome.

Answer 4

1. Scopolamine and atropine
2. Glycopyrrolate
3. Physostigmine

Question 5

• Overdose
  
  • Deliberate or accidental overdose with an anticholinergic drug produces a rapid onset of symptoms characteristic of muscarinic cholinergic receptor blockade.
    
    • The mouth becomes dry, swallowing and talking are difficult, vision is blurred, photophobia is present, and tachycardia is prominent.
    • The skin is dry and flushed, and a rash may appear, especially over the face, neck, and upper chest (blush area).
    • Body temperature is likely to be increased by anticholinergic drugs, especially when the environmental temperature is also increased.
      
      • This increase in body temperature largely reflects inhibition of sweating by anticholinergic drugs, emphasizing that innervation of sweat glands is by sympathetic nervous system nerves that release acetylcholine as the neurotransmitter.
  • Small children are particularly vulnerable to drug-induced increases in body temperature, with “atropine fever” occurring occasionally in this age group after administration of even a _______(1) dose of an anticholinergic drug.
  • Small children and infants seem particularly vulnerable to developing life-threatening symptoms after an overdose with an anticholinergic drug.
    
    • Physostigmine, administered in doses of _______(2) µg/kg IV, is the specific treatment for reversal of symptoms
    • Because physostigmine is metabolized rapidly, repeated doses of this anticholinesterase drug may be necessary to prevent the recurrence of symptoms.

Answer 5

1. therapeutic
2. 15 to 60

Question 6

• Decreased Barrier Pressure
  
  • Barrier pressure is the difference between gastric pressure and lower esophageal sphincter pressure.
    
    • Administration of atropine, 0.6 mg IV, or glycopyrrolate, 0.2 to 0.3 mg IV, decreases lower esophageal sphincter pressure and thus decreases barrier pressure and the inherent resistance to reflux of acidic fluid into the esophagus.
• Benzamides
  
  • The benzamides, aside from their antidopaminergic effects, stimulate the gastrointestinal tract via cholinergic mechanism, which results in:
    
    • (1) contraction of the lower esophageal sphincter and gastric fundus
    • (2) increased gastric and small intestinal motility
    • (3) decreased muscle activity in the pylorus and duodenum when the stomach contracts.
• Metoclopramide
  
  • Because of its antidopaminergic activity, metoclopramide should be used with caution if at all in patients with _______(1) disease, with restless legs syndrome, or who have movement disorders related to dopamine inhibition or depletion
  • In patients with no known movement disorders, dystonic _______(2) reactions (oculogyric crisis, opisthotonus, trismus, torticollis) occur in less than 1% of patients treated chronically with metoclopramide.
    
    • These extrapyramidal reactions are identical to the parkinsonism evoked by antipsychotic drugs.
    • _______(3), a feeling of unease and restlessness may follow the IV administration of metoclopramide, sometimes so severe that it can result in cancellation of surgery or which may manifest in the postanesthesia care unit.

Answer 6

1. Parkinson
2. extrapyramidal
3. Akathisia

Question 7

Benzodiazepines
- The activity of the benzodiazepines is relatively well known, but with respect to a possible mechanism of action in PONV, benzodiazepines may decrease synthesis and release of _______(1) within the CRTZ.
- Perioperative administration of midazolam may reduce PONV by _______(2) to 55%; administration of 2 mg of midazolam IV 30 minutes prior to the end of surgery may be as effective as 4 mg of ondansetron for the treatment of PONV

Butyrophenones
- Butyrophenones are members of the first-generation antipsychotics that exercise their activity via antagonism of the dopamine receptor.
- Aside from antidopaminergic effects, these medications also have _______(3), anticholinergic, and antihistaminergic activity.
- _______(4) After the FDA placed boxed warnings on droperidol due to its association with prolonged QT syndrome, many physicians stopped using droperidol due to its several _______(5) of its efficacy at low dose, the use of droperidol has increased over the last several years as prophylaxis and as rescue therapy as an antiemetic.
- Prophylactic doses of droperidol of 0.625 to 1.25 mg IV are effective for the prevention and treatment of PONV.
- For patients in whom dopamine antagonism is not a concern, droperidol is effective as dexaamethasone or ondansetron in preventing and treating PONV.
- Haloperidol also has antiemetic properties when used in low doses, 0.5 to 2 mg IV. At these doses, sedation does not occur.

Answer 7

1. dopamine
2. 38%
3. antinoradrenergic
4. Droperidol and Haloperidol
5. backlash

Question 8

Neurokinin-1 Antagonists
- Neurokinin-1 antagonists are increasingly used for CINV as chemotherapeutic drugs induce _______(1) release resulting in acute and delayed nausea, which are both attenuated by these medications
- Their effectiveness in CINV patients led to their use in the perioperative management of PONV.
- _______(2) and its prodrug fosaprepitant are the only FDA-approved neurokinin-1 antagonists.
- Common side effects of aprepitant include _______(3), with less common side effects including mucous inflammation, neutropenia, and fever.

Corticosteroids
- Dexamethasone has been shown to be useful in the management of PONV, but the mechanism of antiemetic activity is unclear.
- Corticosteroids are proposed to centrally _______(4) prostaglandin synthesis and control endorphin release.
- It has also been theorized that the antiinflammatory effect of steroids along with the resultant decrease in arachidonic acid release plays a role.
- Obese and diabetic patients are at increased risk for perioperative _______(5) when they receive a single dose of dexamethasone.

Answer 8

1. substance P
2. fosaprepitant
3. headache, fatigue, and constipation
4. inhibit
5. hyperglycemia

Question 9

Histamine Receptor Antagonists
- The effects of histamine are mediated via histaminergic receptors, and at least three histamine receptors subtypes have been identified and classified as H1, H2, and H3.
- Histamine acting through H1 receptors and inositol phospholipid hydrolysis evokes smooth muscle contraction in the gastrointestinal tract.
- In the CNS, histamine receptors are present in the area postrema and vomiting center of the vestibular nucleus along with the nucleus tractus solitarius.
- As such, antihistamines have long been used for treatment and prevention of motion sickness.
- Nonspecific antihistamines, likely acting on H1 receptors including _______(1), dimenhydrinate, cyclizine, and promethazine, are used as antiemetics.
- _______(2) has been used to treat PONV as well as motion sickness.
- _______(3) is another commonly used antihistamine for PONV management.
- The most common side effects from antihistamines are associated to their anticholinergic effects including dry mouth and somnolence

Answer 9

1. diphenhydramine
2. Dimenhydrinate
3. Diphenhydramine